Factors associated with patent foramen ovale-related stroke: SAFAS study.

BACKGROUND: Persistent foramen ovale (PFO) contributes to cryptogenic stroke and is associated with stroke recurrence, although the exact mechanism of ischemic events is not fully understood. Several biomarkers have been developed for the prediction of atrial fibrillation after stroke, but there are currently only limited data on their potential value for the diagnosis of PFO-related stroke. METHODS: This study was a prospective single-center study that included all patients hospitalized between March 31, 2018, and January 18, 2020, in the stroke department of the Dijon University Hospital for ischemic stroke without obvious cause and without a history of atrial fibrillation. PFO was systematically screened by transthoracic echocardiography and images were reviewed by an independent cardiologist blinded from clinical data. PFO was defined according to the CLOSE trial criteria: PFO associated with interatrial septal aneurysm or significant interatrial shunt (> 30 microbubbles in the left atrium within three cardiac cycles after right atrial opacification). The potential association of PFO-related stroke with biomarkers of cardiac fibrosis and inflammation such as galectin-3, GDF-15, ST-2, osteoprotegerin and NT-proBNP was tested using multivariate backward stepwise logistic regression. RESULTS: Of the 240 patients included in the SAFAS study, 229 had complete echocardiographic data, and 23 (10%) had PFO-related stroke. Patients with PFO-related stroke were significantly younger (58±14 vs. 69±14, P<0.001), had less frequent previous arterial hypertension (30 vs. 60%, P=0.008), and more frequent cerebellar territory involvement (26 vs. 9%, P=0.014) compared to the other patients. In addition, they had less frequently left atrial dilatation (left atrial index volume>34mL/m2 [9 vs. 35%, P=0.009]). After ROC curve analysis for definition of thresholds, PFO-related stroke patients more often had galectin-3<9.5ng/mL (59 vs. 27%, P=0.002), ST2<13380pg/ml (23 vs. 50%, P=0.007), GDF-15<1200ng/mL (59 vs. 27%, P=0.002), osteoprotegerin<1133pg/mL (82 vs. 58%, P=0.033) and NT-proBNP<300pg/mL (88 vs. 55%, P=0.009). After multivariate analysis, only galectin-3<9.5ng/mL (OR [95% CI] 3.4 [1.18; 9.8], P=0.024) and osteoprotegerin<1133pg/L (OR [95% CI] 5.0 [1.1; 22.9], P=0.038) were independently associated with PFO-related stroke. CONCLUSION: Patients in whom cryptogenic stroke is attributed to a significant PFO have a specific clinical and biological phenotype. Low levels of galectin-3 and osteoprotegerin may help identify patients with PFO-related strokes.

Gonadotropin-inhibitory hormone in teleosts: New insights from a basal representative, the eel.

Since its discovery in birds, gonadotropin-inhibitory hormone (GnIH) has triggered investigation in the other groups of vertebrates. In the present study, we have identified a single gnih gene in the European eel (Anguilla anguilla), a representative species of a basal group of teleosts (Elopomorphs). We have also retrieved a single gnih gene in Osteoglossomorphs, as well as in more recently emerged teleosts, Clupeocephala. Phylogeny and synteny analyses allowed us to infer that one of the two gnih paralogs emerged from the teleost-specific whole genome duplication (TWGD or 3R), would have been lost shortly after the 3R, before the emergence of the basal groups of teleosts. This led to the presence of a single gnih in extant teleosts as in other vertebrates. Two gnih paralogs were still found in some teleost species, such as in salmonids, but resulting from the additional whole genome duplication that specifically occurred in this lineage (4R). Eel gnih was mostly expressed in the diencephalon part of the brain, as analyzed by quantitative real-time PCR. Cloning of eel gnih cDNA confirmed that the sequence of the GnIH precursor encoded three putative mature GnIH peptides (aaGnIH-1, aaGnIH-2 and aaGnIH-3), which were synthesized and tested for their direct effects on eel pituitary cells in vitro. Eel GnIH peptides inhibited the expression of gonadotropin subunits (lhß, fshß, and common a-subunit) as well as of GnRH receptor (gnrh-r2), with no effect on tshß and gh expression. The inhibitory effect of GnIH peptides on gonadotropic function in a basal teleost is in agreement with an ancestral inhibitory role of GnIH in the neuroendocrine control of reproduction in vertebrates.

First evidence for a direct inhibitory effect of kisspeptins on LH expression in the eel, Anguilla anguilla.

The kisspeptin system has emerged as one of the main puberty gatekeepers among vertebrates. The European eel (Anguilla anguilla) is a remarkable model due to its phylogenetical position at the basis of teleosts, and its unique life cycle with a blockade of puberty before reproductive migration. We cloned the full-length coding sequence of a kisspeptin receptor (Kissr) in the eel. Comparison of Kissr sequences assigned the eel Kissr to a basal position in a clade including most of the known teleost Kissr, in agreement with the eel phylogenetical position. Eel Kissr tissue distribution was analyzed by quantitative real-time PCR. Eel Kissr was highly expressed in the brain, especially in the telencephalon and di-/mes-encephalon, while a very low or undetectable expression was observed in various peripheral organs. A high expression of Kissr was also found in the pituitary indicating a possible direct pituitary role of kisspeptin. Primary cultures of eel pituitary cells were performed to investigate the direct effects of kisspeptin on pituitary hormone expression. Human/lamprey kisspeptin exerted a time- and dose-dependent inhibitory effect on LHß expression. All other tested kisspeptins had a similar inhibitory effect on LHß expression. The inhibitory effect of kisspeptins was exerted specifically on LHß as no change was induced on the expression of other glycoprotein hormone subunits (GPα, FSHß and TSHß) nor of growth hormone. These data provide the first evidence for the existence, in the European eel, of a kisspeptin system, which may play a direct inhibitory role on pituitary LHß expression.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations.

BACKGROUND: Mutations in the transforming growth factor beta receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys-Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent-child pairs with TGFBR1 mutations have been reported to date. METHODS: The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families. RESULTS: Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan-Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations. CONCLUSION: This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.

Identification and stable expression of vitellogenin receptor through vitellogenesis in the European eel.

In teleosts, vitellogenin (Vtg) is a phospholipoglycoprotein synthesized by the liver, released into the blood circulation and incorporated into the oocytes via endocytosis mediated by the Vtg receptor (VTGR) to form the yolk granules. The VTGR is crucial for oocyte growth in egg-laying animals but is also present in non-oviparous vertebrates, such as human. The VTGR belongs to the low-density lipoprotein receptor superfamily (LDLR) and is also named very-low-density lipoprotein receptor (VLDLR). In this study, we identified and phylogenetically positioned the VTGR of a basal teleost, the European eel, Anguilla anguilla. We developed quantitative real-time PCR (qRT-PCR) and investigated the tissue distribution of vtgr transcripts. We compared by qRT-PCR the ovarian expression levels of vtgr in juvenile yellow eels and pre-pubertal silver eels. We also analyzed the regulation of ovarian vtgr expression throughout vitellogenesis in experimentally matured eels. The Vtg plasma level was measured by homologous ELISA experimental maturation. Our in silico search and phylogenetical analysis revealed a single vtgr in the European eel, orthologous to other vertebrate vtgr. The qRT-PCR studies revealed that vtgr is mainly expressed in the ovary and also detected in various other tissues such as brain, pituitary, gill, fat, heart, and testis, suggesting some extra-ovarian functions of VTGR. We showed that vtgr is expressed in ovaries of juvenile yellow eels with no higher expression in pre-pubertal silver eels nor in experimentally matured eels. This suggests that vtgr transcription already occurs during early pre-vitellogenesis of immature eels and is not further activated in vitellogenic oocytes. European eel Vtg plasma level increased throughout experimental maturation in agreement with previous studies. Taken together, these results suggest that vtgr transcript levels may not be a limiting step for the uptake of Vtg by the oocyte in the European eel.

Effect of alpha-tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis.

The ability of alpha-tocopherol to reduce restenosis after angioplasty was tested in a rabbit model in which angioplasty was performed on established atherosclerotic lesions. Lesions induced by 4 wk of cholesterol feeding after focal desiccation of femoral arteries were balloon dilated. 3 wk after angioplasty, angiographically determined minimum luminal diameters were less in the untreated group (0.80 +/- 0.51 mm) than in the group treated with oral alpha-tocopherol beginning 19 d before angioplasty (1.38 +/- 0.29 mm; P < 0.01). The cross-sectional area of the intima-media was greater in the untreated group (1.18 +/- 0.48 mm2) than in the alpha-tocopherol group (0.62 +/- 0.25 mm2, P < 0.0001). These differences were not due to vasoconstriction or altered plasma cholesterol. Alpha-tocopherol thus reduced restenosis after angioplasty in this model. In rabbit vascular smooth muscle cells, oxidized low density lipoprotein stimulated DNA synthesis. Alpha-tocopherol treatment inhibited DNA synthesis stimulated by oxidized low density lipoprotein, but not by serum. The findings are consistent with the hypothesis that oxidized lipids can stimulate hyperplasia and that antioxidants may limit hyperplasia by inhibiting either the oxidation or the proliferative effects of oxidants on cells.

[Gp IIb/IIIa receptor antagonists in acute coronary syndromes with no ST elevation]. / Antagonistes des récepteurs Gp IIb/IIIa dans les syndromes coronaires aigus sans sus décalage du segment ST.

Gp IIb/IIIa receptor antagonists have been the subject of much work in patients presenting with acute coronary syndrome with no ST elevation (ACS ST-). The initial studies (PRISM, PRISM-PLUS, PURSUIT, PARAGON, CAPTURE, GUSTO IV-ACS) were performed at the end of the 1990s and universally showed a significant reduction in an endpoint combining death and myocardial infarction, especially in patients with an elevation of troponin and treated by angioplasty. However, these studies were performed at a time when clopidogrel was not being used regularly for this indication. Four randomised studies have recently re-evaluated the significance of Gp IIb/IIIa blockers prescribed either on admission to coronary intensive care (ELISA-2, PRACTICE) or in the coronary angiography suite during angioplasty (ADVANCE, ISAR-REACT 2) in patients presenting with ACS ST- pre-treated with clopidogrel in association with aspirin and heparin. The results of these studies suggest that Gp IIb/IIIa blockers initiated at the start of angioplasty significantly reduce an endpoint combining death, myocardial infarction and the need for emergency revascularisation. On the other hand, studies in which Gp IIb/IIIa blockers are initiated in coronary intensive care have been negative, but they have only been carried out on small numbers. The results of the ACUITY study comparing bivalirudin and Gp IIb/IIIa blockers in this context have recently been published. Bivalirudin seems to compare well with Gp IIb/IIIa blockers in terms of ischemia, but it significantly reduces the occurrence of hemorrhagic events.

In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion.

BACKGROUND: The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS: Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. CONCLUSIONS: In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.

Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty.

BACKGROUND: Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling. METHODS AND RESULTS: Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study. CONCLUSIONS: These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

The smooth muscle cell: sinner or saint in restenosis and the acute coronary syndromes?

Proliferation of arterial smooth muscle cells has held center stage as the culprit in restenosis for almost two decades. Many strategies for combating restenosis target smooth muscle replication. However, none have proven beneficial in clinical trials. Indeed, inhibition of smooth muscle proliferation in human patients might produce the undesired effect of destabilizing vulnerable atherosclerotic plaques because these cells furnish the collagen responsible for the biomechanical strength of the plaque. Actually, in some cases the benefit of angioplasty may depend on stimulating smooth muscle replication and collagen elaboration, converting an "unstable" to a more stable plaque. Moreover, recent clinical and experimental evidence suggests that restenosis depends less on neointimal hyperplasia than on constrictive remodeling (i.e., advential scarring, producing a smaller lumen), a process independent of smooth muscle replication. The recognition that plaques vulnerable to disruption often do not produce flow-limiting stenoses highlights a need for reassessment of the strategies to treat or prevent the acute coronary syndromes. We should strive to treat aggressively risk factors such as hyperlipidemia whose control appears to stabilize plaques. Trials are even underway comparing such risk factor management with coronary artery intervention. If we could identify potentially unstable atheroma before they are evident, clinically, we might even contemplate angioplasty of nonsignificant stenoses to induce smooth muscle cell proliferation and reinforce the plaque's fibrous cap. This proposal may seem preposterous, yet we perform "primary" angioplasty every day in patients with an acute myocardial infarction whose "culprit" lesions underlying the thrombus are often not critical. Our knowledge of the biology of restenosis has lagged behind our practice of coronary intervention. Advances in understanding the biology of the complications of interventional therapy, hand in hand with technical advances, should help us to devise more rational and enduring approaches to benefiting our patients.

Protection against ischemia during prolonged balloon inflation by distal coronary perfusion with use of an autoperfusion catheter or Fluosol.

OBJECTIVES: The purpose of this report was to study the protective effects of passive and active distal coronary perfusion during prolonged balloon inflation. BACKGROUND: Prolonged balloon inflation has been proposed to improve immediate and long-term results of percutaneous transluminal coronary angioplasty, but it requires protection against myocardial ischemia. METHODS: A 30-min balloon occlusion of the left anterior descending artery was performed in three groups of closed chest anesthetized dogs: 1) control (no distal coronary perfusion, n = 13), 2) passive distal coronary perfusion (autoperfusion catheter, n = 10), and 3) active distal coronary perfusion (infusion of the perfluorochemical Fluosol at 30 ml/min, n = 11). RESULTS: At 10 min of balloon inflation, echocardiographic wall motion indexes (scored from 1 [normal] to 5 [dyskinesia]) in the autoperfusion catheter and Fluosol groups (2.4 +/- 1.2 and 2.0 +/- 0.9, respectively) were significantly better than in the control group (3.6 +/- 0.4, p = 0.001), but at 25 min this improvement in wall motion had attenuated and became statistically insignificant when compared with values in the control group. Left ventricular end-diastolic pressure at peak inflation in the Fluosol group (19.5 +/- 5.5 mm Hg) was higher than in the control (7.6 +/- 3.6) and autoperfusion catheter (5.3 +/- 1.4, p < or = 0.01) groups. Pathologic evidence of infarction by tetrazolium staining was seen in three control dogs and in none of the other groups (p = 0.07). Ventricular tachycardia and fibrillation were less frequent in the autoperfusion catheter group (p = 0.02). Three deaths were observed in the control dogs, two in the Fluosol group and none in the dogs with an autoperfusion catheter (p = NS). CONCLUSIONS: Passive (the autoperfusion balloon catheter) and active (Fluosol) distal coronary perfusion methods are comparable and better than no perfusion in protecting the myocardium against ischemia produced by prolonged coronary balloon inflation in an experimental canine model. This protection is transient, attenuating after 10 to 25 min, and partial because there was no significant difference in the incidence of myocardial infarction and death among groups, although the latter observations may be related to small sample size.

Percutaneous transluminal coronary angioplasty of one major coronary artery when the contralateral vessel is occluded.

OBJECTIVES: In 193 patients we evaluated the safety and efficacy of angioplasty of a critical stenosis of the right coronary artery (52 patients) or the left anterior descending coronary artery (141 patients), with the contralateral coronary artery occluded and the circumflex artery being without significant stenosis. BACKGROUND: Attempted angioplasty of either the left anterior descending or the dominant right coronary artery when the contralateral vessel is occluded may trigger overwhelming left ventricular dysfunction or hemodynamic collapse, or both. METHODS: Immediate and late outcome (33 +/- 18 months) in the study group were compared with outcome in 214 patients who had angioplasty in both the left anterior descending and right coronary arteries and in 194 patients who had coronary artery surgery and were matched for number and location of significant lesions, ejection fraction, age, gender and study period. RESULTS: Left ventricular function was normal (38%) or mildly (34%), moderately (22%) or severely (6%) compromised. There were 11 (5.7%) emergency and 5 (2.6%) elective coronary artery operations, 3 (1.6%) myocardial infarctions and 1 in-hospital death in the study group. After discharge there were 25 (13.1%) elective coronary operations, 7 (3.7%) myocardial infarctions and 9 (4.7%) deaths in the study group. The incidence of death and myocardial infarction was similar in all groups, with 80% power to detect a 7% difference in adverse events. The study group had more elective surgery before and after discharge than did the surgical control group (p = 0.02). CONCLUSIONS: Dilating one major vessel when the contralateral vessel is occluded appears to be as safe as coronary surgery or two-vessel angioplasty. Incomplete revascularization in study group patients did not impair survival or increase myocardial infarction compared with the angioplasty and surgical control groups.

Effect of Buckberg cardioplegia and peripheral cardiopulmonary bypass on infarct size in the closed chest dog.

OBJECTIVES: To simulate a human catheterization laboratory setting of controlled reperfusion during myocardial infarction, regional infusion of commercially available Buckberg cardioplegic solution and peripheral vented bypass were administered in the closed chest dog. BACKGROUND: Studies in open-chest dogs have demonstrated a significant reduction in infarct size and improvement in regional wall motion with a similar controlled reperfusion method using infusion of substrate-enriched (Buckberg) cardioplegic solution during cardiopulmonary bypass coupled with left ventricular venting. METHODS: After 100 or 180 min of balloon occlusion of the proximal left anterior descending artery, controlled reperfusion was performed with cardioplegic infusion and vented bypass. Dogs matched for occlusion time underwent balloon deflation without bypass or cardioplegia (uncontrolled reperfusion groups). Microspheres were used to quantify coronary ischemia during balloon inflation. All four groups (n = 8 to 9 per group) were followed up at 1 week to determine regional wall motion and infarct size. RESULTS: Qualitative echocardiographic analysis demonstrated no significant difference among groups in recovery of regional wall motion at 1 week; however, wall motion improved significantly in all groups between the ischemia and 1-week recovery periods. The histologic infarct size compared with the area at risk for dogs with uncontrolled versus controlled reperfusion, respectively, was 17.9 +/- 10.5% versus 31.9 +/- 8.3% (p < 0.05) for dogs with 100 min of occlusion and 40.1 +/- 11.7% versus 46.2 +/- 8.4% (p = NS) for dogs with 180 min of occlusion. A greater rate-pressure product in the dogs with controlled reperfusion after 100 min of occlusion (p < 0.05) may explain the larger infarct size observed for that group. CONCLUSIONS: These results demonstrate that regional infusion of substrate-enriched cardioplegic solution in combination with peripheral vented bypass does not further reduce infarct size after prolonged ischemia in the closed chest dog (compared with uncontrolled reperfusion).

A comparison of systematic stenting and conventional balloon angioplasty during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction. STENTIM-2 Investigators.

OBJECTIVES: In a multicenter, randomized trial, systematic stenting using the Wiktor stent was compared to conventional balloon angioplasty with provisional stenting for the treatment of acute myocardial infarction (AMI). BACKGROUND: Primary angioplasty in AMI is limited by in-hospital recurrent ischemia and a high restenosis rate. METHODS: A total of 211 patients with AMI <12 h from symptom onset, with an occluded native coronary artery, were randomly assigned to systematic stenting (n = 101) or balloon angioplasty (n = 110). The primary end point was the binary six-month restenosis rate determined by core laboratory quantitative angiographic analysis. RESULTS: Angiographic success (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 and residual diameter stenosis <50%) was achieved in 86% of the patients in the stent group and in 82.7% of those in the balloon angioplasty group (p = 0.5). Compared with the 3% cross-over in the stent group, cross-over to stenting was required in 36.4% of patients in the balloon angioplasty group (p = 0.0001). Six-month binary restenosis (> or = 50% residual stenosis) rates were 25.3% in the stent group and 39.6% in the balloon angioplasty group (p = 0.04). At six months, the event-free survival rates were 81.2% in the stent group and 72.7% in the balloon angioplasty group (p = 0.14), and the repeat revascularization rates were 16.8% and 26.4%, respectively (p = 0.1). At one year, the event-free survival rates were 80.2% in the stent group and 71.8% in the balloon angioplasty group (p = 0.16), and the repeat revascularization rates were 17.8% and 28.2%, respectively (p = 0.1). CONCLUSIONS: In the setting of primary angioplasty for AMI, as compared with a strategy of conventional balloon angioplasty, systematic stenting using the Wiktor stent results in lower rates of angiographic restenosis.

The French Randomized Optimal Stenting Trial: a prospective evaluation of provisional stenting guided by coronary velocity reserve and quantitative coronary angiography. F.R.O.S.T. Study Group.

OBJECTIVES: We sought to make a prospective comparison of systematic stenting with provisional stenting guided by Doppler measurements of coronary velocity reserve and quantitative coronary angiography. BACKGROUND: Despite the increasing use of stents during percutaneous transluminal coronary angioplasty, it is unclear whether systematic stenting is superior to a strategy of provisional stenting in which stents are placed only in patients with unsatisfactory results or as a bail-out procedure. METHODS: Two hundred fifty-one patients undergoing elective coronary angioplasty were randomly assigned either to provisional stenting (group 1, in which stenting was performed if postangioplasty coronary velocity reserve was <2.2 and/or residual stenosis > or =35% or as bail-out) or to systematic stenting (group 2). The primary end point was the six-month angiographic minimal lumen diameter (MLD). Major adverse cardiac events were secondary end points (death, acute myocardial infarction and target lesion revascularization). RESULTS: Stenting was performed in 48.4% of patients in group 1 and 100% of patients in group 2 (p<0.01). Six months after angioplasty, the MLD did not differ between groups (1.90+/-0.79 mm vs. 1.99+/-0.70 mm, p = 0.39), as was the rate of binary restenosis (27.1% vs. 21.4%, p = 0.37). Among patients with restenosis, 13/32 (40.6%) in group 1 but 100% (25/25) in group 2 had in-stent restenosis (p<0.01). Target lesion revascularization (15.1% vs. 14.4% in groups 1 and 2 respectively, p = 0.89) and major adverse cardiac events (15.1% vs. 16.0%, p = 0.85) were not significantly different. CONCLUSIONS: Systematic stenting does not provide superior angiographic results at six months as compared with provisional stenting.

[Coronary angioplasty in the acute phase of a myocardial infarction on a myocardial bridge]. / Angioplastie coronaire à la phase aiguë d'un infarctus du myocarde sur pont myocardique.

A myocardial bridge is usually asymptomatic but can cause myocardial ischemia, myocardial infarction or sudden death. Two occurrences of coronary angioplasty in the acute phase of an anterior myocardial infarction on a myocardial bridge are reported. The first case was first treated only with a balloon, and then with a stent 12 h later after a relapse of angina pectoris and the recurrence of a severe compression. The second case immediately benefited from a stent. A systematic control at six months has shown the absence of restenosis in the first case and an asymptomatic occlusion of the stent in the second case. Its deocclusion has revealed a myocardial bridge downstream of the stent. Myocardial stunning might have caused a decreased systolic compression by the bridge in the first case, and an underestimation of its actual length in the second case. Its regression is held responsible for these two relapses. A long active stent installed at high pressure could be used to treat myocardial bridges during myocardial infarctions.

[Anticoagulants and dental extractions]. / Anticoagulants et extractions dentaires.

Dental extractions in patients under platelet antiaggregant or anticoagulant therapy pose the problem of risk benefit between stopping or carrying on treatment. The difficulties of reequilibrating the INR after a heparin relay have led surgeons and cardiologists to look for alternative solutions. Different means of local haemostasis using products with haemostatic properties or not, or the use of sutures or glues, have given encouraging results but there is too much uncertainty for systematic recommendations to practicians responsible for dental extractions in these patients. The authors propose a technique which has the advantages of associating systematically different methods, making bleeding complications very unusual, without interrupting anticoagulant or antiaggregant therapy.

Vasomotor dysfunction early after exposure of normal rabbit arteries to an adenoviral vector.

We aimed to investigate whether infection of normal rabbit arteries with a recombinant adenovirus vector would result per se in alterations in contractile and endothelial functions. In one group of rabbits, right or left femoral and ear artery segments were injected in vivo with a replication-deficient adenoviral vector expressing a beta-galactosidase (beta-Gal) reporter gene (4 x 10(10) pfu/ml) to demonstrate efficient gene transfer. Contralateral arteries were injected with the same concentration of a recombinant adenoviral vector carrying no transgene (Ad.MLPnull). In another group of animals, Ad.MLPnull was injected into the lumen of femoral and ear artery segments. The contralateral arteries were used as controls with the injection of vehicle alone. Histochemical assessment of gene transfer using beta-Gal activity (group 1) or in vitro contractility and endothelial function (group 2) was performed 3 days after adenoviral infection. Gene transfer was efficient and reproducible in the endothelium and was associated with the presence of inflammatory cells in the media. In Ad.MLPnull-injected arteries, in vitro contractile response of femoral artery rings to either KCl 60 mM or phenylephrine (10 microM) was reduced to 10.5 +/- 2.3% (n = 14; p < 0.001) and 8.8 +/- 2.0% (n = 7; p < 0.001) of the control values, respectively. Furthermore, in arteries injected with Ad.MLPnull, the endothelium-dependent relaxation produced by acetylcholine (10 microM) was virtually abolished. Similarly, the relaxant effects of the alpha 2-adrenoreceptor agonist UK14304 (1 microM) or the Ca2+ ionophore A23187 (1 microM) were also abolished. By contrast, sodium nitroprusside (10 microM) was still able to relax adenovirus-infected arteries. We conclude that infection with a recombinant adenoviral vector can induce early severe vasomotor alterations in both contractile function and endothelium-mediated relaxation of normal rabbit arteries.

Thrombus generation after adenovirus-mediated gene transfer into atherosclerotic arteries.

Thrombosis represents a major issue during arterial local delivery. We evaluated the occurrence of thrombosis after adenovirus (Ad)-mediated gene transfer into normal and atherosclerotic arteries. A replication-deficient Ad vector expressing the beta-galactosidase reporter gene (Ad.RSV betagal; 4 x 10(9) PFU) was injected into normal and atherosclerotic arteries (n = 11 in both groups). The contralateral artery received either an Ad vector carrying no transgene (Ad.MLPnull) (n = 7 in both groups, 4 x 10(9) PFU) or vehicle buffer (n = 4 in normal group, n = 8 in atherosclerotic group). Animals were sacrificed 3 days following gene transfer for thrombus detection and assessment of beta-galactosidase activity. Thrombus was absent in normal arteries and in atherosclerotic arteries injected with vehicle buffer only. In contrast, nonocclusive thrombus was present in atherosclerotic arteries injected with either Ad.RSV betagal (5 of 11) or Ad.MLPnull (3 of 7). Beta-galactosidase activity was predominantly found in the endothelial layer of the transfected arteries. Gene transfer and expression occurred despite the presence of the thrombus (4 of 5), and its efficiency did not significantly differ regardless of the thrombus. We conclude that thrombus frequently occurred in atherosclerotic arteries after Ad-mediated gene transfer. Further studies are warranted to identify the mechanisms of thrombus generation after Ad-mediated gene transfer into atherosclerotic arteries.